Pharmaceutical compositions containing 4-substituted imidazoles to be administered transdermally

ABSTRACT

This invention relates to a transdermal preparation comprising a therapeutically active compound of the formula: ##STR1## where R 1 , R 2 , and R 3 , which can be the same or different are H, CH 3 , C 2  H 5  or Cl; X is CH═CH or (CH 2 ) n  where n is 1 to 3 or X is --C(OR 5 )H-- where R 5  is methyl or ethyl; and R 4  is hydrogen or a straight alkyl of 1 to 4 carbon atoms. The transdermal administration of the compounds can be accomplished by preparations in the form of ointments, emulsions, lotions, solutions, creams or transdermal patches.

This invention relates to the use of certain known therapeuticallyactive imidazoles substituted in the 4-position for use in themanufacture of pharmaceutical preparations for transdermaladministration. Such transdermal preparations are also within the scopeof the invention.

The therapeutically active 4-substituted imidazoles have the generalformula ##STR2## where R₁, R₂ and R₃ which can be the same or differentare H, CH₃, C₂ H₅ or Cl; X is CH═CH or (CH₂)_(n) where n is 1 to 3 or Xis --C(OR₅)H-- where R₅ is methyl or ethyl; and R₄ is hydrogen or astraight alkyl of 1 to 4 carbon atoms.

Members of formula (I) and (II) are well known potent and selective α₂-adrenoceptor active agents. Compounds of formula (I) are α₂-adrenoceptor agonists while compounds of formula (II) are α₂-adrenoceptor antagonists. Based on these pharmacological features thecompounds are useful in a wide field of therapy. Compounds of formula(I) are disclosed e.g. in the European Patent Publications 24829, 34473,34474, and 72615 and compounds of formula (II) are described in EP198492. EP 24829 discloses various members of formula (I) having X beingCH₂ or --C(OR₅)H-- as active antihypertensive, antiulcer, diuretic,tranquilizing, sedative, analgesic and anti-inflammatory agents. Onemember, 4-(2,3-dimethylbenzyl)-1H-imidazole, the generic name of whichis detomidine, is commercially used as a veterinary sedative injectionpreparation to be used in the treatment of big animals, especiallyhorses. EP 34473 discloses componds of formula (I) where X is (CH₂)_(n)and n is greater than 1 as valuable agents for the treatment ofhypertension. EP 34474 discloses compounds of formula (I) where X isCH═CH as valuble antihypertensive, antithrombotic, antifungal andantimicrobial agents. EP 72615 describes i.a. compounds of formula (I)where X is --C(CH₃)H-- as useful antihypertensive agents. One member,4-[α-methyl-2,3-dimethylbenzyl-1H-imidazole the generic name of which ismedetomidine, has further been disclosed in U.S. Pat. No. 4,783,477 andhas been commercialized as a veterinary sedative-analgesic injectionpreparation for small animals. EP 183492 discloses members of formula(II) as useful α₂ -adrenoceptor antagonists. Atipamezole, which is thecompound of formula (II) where R₄ is ethyl, is described in said patentto be useful for the reversal of detomidine. The compound is alsomarketed as an injection preparation for this purpose, especially as areversal for medetomidine. EP 183492 suggests moreover a great many usesof the compounds of formula (II) e.g. antidiabetic, antidepressive andantiasthmatic uses.

In many therapeutic uses a steady, uniform administration of the activeagent is desirable. Many compounds, especially those of formula (II) areknown to have a rather poor bioavailability due to extensive initialmetabolism of the drug. These compounds would not therefore be suitablefor oral administration. In many fields of therapy injections are,however, not convenient. Transdermal administration is one alternativein such cases as it combines the convenience of oral administration andthe high bioavailability of injections.

The present invention relates to transdermal administration of compoundsof formula (I) and (II) as well as suitable preparation therefore.

Only a minor part of commercially available therapeutically activesubstances is suitable for transdermal administration due to manydifferent pharmacokinetic and pharmacological reasons. One of the mostlimiting factors is, however, the physicochemical properties of thetherapeutically active substance itself. For a compound to be able topenetrate the skin it must have both lipophilic (fat soluble) andhydrophilic (water soluble) properties in a suitable proportion. Such asuitable ratio between the lipophilic and hydrophilic properties is notvery common for drug substances. The ability of a drug to penetratethrough the skin can be predicted by its partition coefficient P inoctanol/water. It is known that compounds having an optimal partitioncoefficient penetrate the skin better than compounds with either higheror lower partition coefficients. This optimal partition coefficientvalue is different for different kinds of compounds.

Compounds of formula (I) and (II) have proved to possess optimalpartition coefficients thus rendering them suitable for transdermaladministration.

BRIEF DESCRIPTION OF THE DRAWING

The transdermal administration of the compounds of formula (I) and (II)can be accomplished in two different ways: (i) by mixing thetherapeutically active compounds with suitable pharmaceutical carriersand optionally penetration enhancers to form ointments, emulsions,lotions, solutions, creams, gels, patches or the like, where preferablya fixed amount of said preparation should be applied onto a certain areaof skin, or (ii) by incorporating the therapeutically active substanceinto a transdermal delivery system according to one of the alternativesdisclosed in FIGS. 1A, 1B and 1C. Transdermal drug delivery devices canbe categorized into three general types (FIGS. 1A, 1B, and 1C). FIG. 1Adiscloses a transdermal device comprising (a) a drug impermeable backinglayer and (b) an adhesive layer that fixes the bandage to the skin. Inthis preparation the drug is mixed in the adhesive layer. FIG. 1Brepresents a device incorporating a backing layer (a), an adhesive layer(b) and a matrix layer (c) preferably made of a polymer material inwhich the drug is dispersed. The rate of which the drug is released fromthe device is here controlled by the polymer matrix. A third kind ofdevice is the reservoir system according to FIG. 1C comprising (a) adrug impermeable backing layer; an adhesive layer (b); a drug permeablemembrane (d) sealed to one side of said backing layer as to define atleast one drug reservoir compartment there between, and (e) a drug orcomposition thereof within said drug reservoir. In this case the drug inthe reservoir is usually in liquid or gel form. The drug permeablemembrane controls the rate at which the drug is delivered to the skin.

By the term "suitable pharmaceutical carrier" is meant a non-toxicpharmaceutically acceptable vehicle including for example polyethyleneglycol, propylene glycol, isopropanol, ethanol, oleic acid,N-methylpyrrolidone, sesame oil, olive oil, wood alcohol ointments,vaseline and paraffin or a mixture thereof.

Suitable penetration enhancers include for example saturated andunsaturated fatty acids and their esters, alcohols, monoglycerides,diethanolamines, N,N-dimethylamines such as linolenic acid, linolenylalcohol, oleic acid, oleyl alcohol, stearic acid, stearyl alcohol,palmitic acid, palmityl alcohol, myristic acid, myristyl alcohol,1-dodecanol, 2-dodecanol, lauric acid, decanol, capric acid, octanol,caprylic acid, 1-dodecylazacycloheptan-2-one sold under the trademarkAZONE, ethyl caprylate, isopropyl myristate, hexamethylene lauramide,hexamethylene palmitate, capryl alcohol, decyl methyl sulfoxide,dimethyl sulfoxide, salicylic acid and its derivatives,N,N-diethyl-m-toluamide, crotamiton, 1-substituted azacycloalkan-2-ones,polyethylene glycol monolaurate and any other compounds compatible withthe therapeutically active compounds of formula (I) and (II) and thepackages and having transdermal permeation enhancing activity.

Preferred administration rates of the drug is 0.1-1000 μg/h through askin area of about 2-90 cm², preferably 10-30 cm². The amount of drugdelivered into the skin can be controlled by a number of factorsincluding skin patch size, degree of drug loading, the use of ratecontrolling membranes, permeation enhancers etc.

The backing layer can be flexible or nonflexible and suitable materialsinclude for example cellophane, cellulose acetate, ethylcellulose,vinylacetate-vinylchloride copolymers, polyethylene terephthalate,nylon, polyethylene, polypropylene, polyester films, polyvinylidenechloride, coated flexible fibrous backings such as paper and cloth andaluminium foil.

The adhesive layer comprises for example polysiloxanes,polyisobutylenes, polyacrylates, polyurethanes, ethylene-vinyl acetatecopolymers, polyether amide block polymers, polyisobutene,polystyrene-isoprene copolymers, polystyrene-butadiene copolymers.Preferred adhesives are acrylates, silicones and polyurethanes.

The drug permeable membrane can be made of materials includingpolyethylene, polypropylene, ethylene vinyl acetate copolymers,polycarbonates, polyvinyl chloride, polyacrylate polymers, polysulfonepolymers, polyvinylidienes, polyvinylidenes, polyesters andpolyisobutylenes, for example.

The matrix is preferably an anhydrous matrix such as natural orsynthetic rubbers or other polymeric material, thickened mineral oil orpetroleum jelly, for example. A preferred embodiment is anethylene/vinylacetate copolymer.

EXPERIMENTS

Analytical HPLC Method

The fully automated (Hewlett-Packard, USA) liquid chromatographconsisted of a pump 1090, an autosampler and autoinjector (79847A) and afixed wavelength UV detector, 210 nm (79881A). The chromatograms,retention times and peak areas were recorded with an integrator 3393.The separations were carried out at a column temperature of 37° C. on a35 * 4.6 mm stainless steel column (packed with a 3-μm sphericaloctadecyl-silane-bonded silica particles; HS-3 C-18, (Perkin-Elmer,USA). The mobile phase consisted of different mixtures of acetonitrile:0.05M aqueous phosphate buffer pH 7.4 containing 0.004M of dimethyloctylamine. The flow rate was 0.8 ml/min.

Shake-flask Apparent Partition Coefficient Method

The apparent partition coefficient P' (the partition coefficient P forionic compounds in partly ionized state) was determined for thedifferent arylalkyl imidazole compounds at different pH- values (7.4,3.0, about 5, 7 and 9) according to the following procedure: thecompounds were dissolved in octanol-saturated phosphate buffer (0.1M,with the appropriate pH) using as a modified method the one describedfor clonidine and structurally related imidazoles (Timmermans et alNaunyn-Schmid. Arch. Pharmacol. 300, p. 217, 1977) the startingconcentrations in the aqueous phosphate buffer being 200 μM. The aqueousphase was shaken with buffer-saturated n-octanol (the volumes being foraqueous buffer and octanol either 10:1 or 20:1) for one hour at roomtemperature (20°-22° C.) and then equilibrated by allowing to stand for20 hours. At least three parallel tests were made in each case. Sampleswere taken from the aqueous phase and the concentration of the compoundwas analyzed according to the HPLC method described above. The apparentpartition coefficient (P') at a certain pH can be calculated from thefollowing equation:

    P'=(C.sub.0 -C.sub.1)V.sub.Aq /C.sub.1 V.sub.Oct

C₀ is the initial and C₁ is the final (after partioning) concentrationof the tested compound in the aqueous phase. V_(Aq) and V_(Oct) are thevolumes of the aqueous respectively the octanol phase.

IN VITRO SKIN PERMEATION MEASUREMENTS

Treatment of Skin Samples

All of the penetration and skin/solvent partition experiments reportedhere utilized human skin from the thigh region obtained at autopsy. Theskin samples (with the thickness of about 1 mm) containing the epidermisand a part of dermis were taken with a dermatome (Elemo HM94,Switzerland). The epidermis was separated from the dermis by the methodof Chandrasekaran et al (Am. I. Chem. Eng. J. 22 p. 828, 1976) bykeeping the skin in hot water (60° C.) for 60 seconds. After isolationthe epidermis was dried between two sheets of paper, cut into smallerpieces and stored in aluminium foil in polyethylene bags at 4° C. for nomore than 4 weeks.

Permeation Experiments

Two different kinds of diffusion cells were used in the experiments:Franz type of diffusion cell, finite dose technique (Franz, Curr. Probl.Dermatol. 7, p. 58, 1978), (FDC-400, diffusion area 1.77 cm², receivercompartment volume 11.5-12.0 ml, Crown Glass Company, Inc. USA) was usedfor the testing of the ointment and for the polymer formulation. For allthe other experiments diffusion cells of type DC 100B Side-Bi-Side wasused, diffusion area 0.79 cm², donor and receiver compartment volume 3.4ml, Crown Glass Company Inc. USA. The stirring (500 rpm) of the magnetbar was generated for both type of cells with a drive console (VSG-1,Crown Glass Company Inc. USA). Both types of cells were made of glassand were jacketed for temperature control 37° C. (MGW Lauda, type MS,Germany).

The stored skin (epidermis) samples were checked visually andmicroscopically for defects before use. In the permeation experiment theepidermis sample was clamped between the two parts of the cell system.To be able to prevent any leakages the four corners of the epidermissample extended outside the contact area of the system. The epidermissample was hydrated from both sides over night, with aqueous phosphatebuffer 0.05M pH 7.4 (6.9 g NaH₂ PO₄ *H₂ O/l of water, pH adjusted to 7.4with 10M NaOH) on the receiver side (viable epidermis side) and on thedonor side (stratum corneum side) with the same solvent, ointment orpatch (without the penetrant) to be used as the donor formulation of thepenetrant in the actual skin permeation experiment. Next morning afterhydrating the skin overnight the permeation experiment started by firstremoving the donor formulation and the receiver solutions from thediffusion cell: fresh aqueous phosphate buffer pH 7.4 was added to thereceiver side (FDC-400 11.5 ml and DC 100B 3.4 ml) and a formulationvolume now containing a known amount of penetrant molecule was added tothe donor side. Particular care was taken to prevent air bubbles fromforming on the surface of the skin. 1.0 ml samples (DC 100B) and 0.4 ml(FDC-400) were withdrawn from the receiver chamber at intervals andreplaced with the same volume of fresh receiver solution. The sampleswere then analyzed according to the HPLC method described above.Corrections were made (for the losses from earlier samplings) incalculating the cumulative amount of drug that permeated the skin. Thepermeation of the penetrant through epidermis was described by a plot ofcumulated amount of penetrant Q (in μg) vs time in hours. The slope ofthe curve and the intercept on the x-axis (lag time) were determined bylinear regression. Penetrant flux J (in μg/cm² h) was calculated fromthe slope μg penetrant/h and knowing the area of the skin surfacethrough which diffusion was taking place (cm²) (Flynn et al, CRC Press,Boca Raton, Fla., p. 45, 1987). The permeability constant k_(p) wascalculated from the formula k_(p) =J/C where J represents thesteady-state flux and C the donor concentrations. The results arepresented in Tables I to VII.

Three different kinds of ointments of two of the compounds tested (codenr 253 AII and 1248) were prepared: an aqueous ointment (1), ahydrophilic (2) and a lipophilic (3) one, VI--VI. Table VII discloses anexample of a patch formulation illustrating the invention.

                  TABLE I                                                         ______________________________________                                        Molecular structure of arylalkyl imidazole compounds tested.                   ##STR3##                      (I)                                            No   Compound  A.sub.1  A.sub.2                                                                            A.sub.3                                                                            A.sub.4                                                                             A.sub.5                                                                             A.sub.6                         ______________________________________                                        1    247 AII   CH.sub.2 H    H    H     CH.sub.3                                                                            H                               2    248 AII   CH.sub.2 H    H    CH.sub.3                                                                            H     H                               3    207 AIV   CH.sub.2 CH.sub.3                                                                           H    H     H     CH.sub.3                        4    253 AII   CH.sub.2 H    H    H     CH.sub.3                                                                            CH.sub.3                        5    867 AII   CH.sub.2 H    CH.sub.3                                                                           H     H     CH.sub.3                        6    254 AII   CH.sub.2 H    H    CH.sub.3                                                                            CH.sub.3                                                                            H                               7    257 CIII  CH.sub.2 Cl   H    H     H     Cl                              8    207 AVI                                                                                  ##STR4##                                                                              CH.sub.3                                                                           H    H     H     CH.sub.3                        9    1248    atipamezole                                                      10   305 BII   CHCH     CH.sub.3                                                                           H    H     H     CH.sub.3                        11   304 AII   (CH.sub.2).sub.3                                                                       CH.sub.3                                                                           H    H     H     CH.sub.3                        12   1424 AII  CH.sub.2 H    H    H     Cl    Cl                              ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Effect of pH of the donor solution on                                         the percutaneous absorption of 253 AII                                        through human cadaver epidermis at 37° C.                                          Ioniz.                                                                Conc.   degree  Flux ± SD                                                                          k.sub.p *10.sup.-4                                                                   Enhanc.                                    pH  mg/ml   %       μg/cm.sup.2 h                                                                      cm/h   factor Log P'                              ______________________________________                                        3.0 245.00  100.0   1.07 ± 0.33                                                                         0.04   1     -0.66                               5.1  34.39   98.9   2.13 ± 0.48                                                                         0.62   14    0.67                                6.9  1.00    59.1   1.73 ± 0.15                                                                        17.25  394    nd                                  8.8  0.45    1.8    1.73 ± 0.47                                                                        38.65  883    2.81                                ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Effect of pH of the donor solution on                                         the percutaneous penetration of 1248                                          through human cadaver skin at 37° C.                                               Ioniz.                                                                Conc.   degree  Flux ± SD                                                                          k.sub.p *10.sup.-4                                                                   Enhanc.                                    pH  mg/ml   %       μg/cm.sup.2 h                                                                      cm/h   factor Log P'                              ______________________________________                                        3.0 35.20   100.0   0.09*   <0.03    1    -0.33                               5.0 10.18    99.2   0.37 ± 0.03                                                                        0.37    14    1.02                                7.4  0.30    33.4   1.55 ± 0.31                                                                        52.30  1958   3.05                                9.1  0.10    1.0    0.52 ± 0.14                                                                        53.47  2002   3.66                                ______________________________________                                         *n = 1                                                                        The enhancing factor in Tables II to III is calculated as the ratio           k.sub.p *10.sup.-4 at pH 3.0:k.sub.p *10.sup.-4 at the current pH        

                  TABLE IV                                                        ______________________________________                                        Percutaneous penetration parameters and skin: buffer partition                coefficients log P' of arylalkyl imidazole compounds through                  human cadaver epidermis at pH 7.4, 37° C.                                             Flux ± SD                                                                            Lag time                                                                              k.sub.p *10.sup.-3                           No   Compound  μg/cm.sup.2 h                                                                        h       cm/h   Log P'                                ______________________________________                                        1    247 AII   26.7 ± 5.4                                                                           1.0     5.5    2.21                                  2    248 AII   27.1 ± 2.2                                                                           1.0     5.9    2.26                                  3    207 AIV   40.3 ± 0.4                                                                           1.0     10.1   2.55                                  4    253 AII    4.0 ± 0.6                                                                           3.0     2.7    2.50                                  5    867 AII   13.0 ± 4.2                                                                           2.0     6.8    2.54                                  6    254 AII   36.8 ± 2.9                                                                           1.3     14.7   2.54                                  7    257 CIII   2.9 ± 0.7                                                                           1.7     2.8    2.96                                  8    207 AVI    1.9 ± 0.2                                                                           2.0     1.6    2.65                                  9    1248       1.6 ± 0.3                                                                           2.9     4.1    3.05                                  10   305 BII    4.9 ± 0.6                                                                           1.0     11.9   3.00                                  11   304 AIII  13.8 ± 3.3                                                                           1.0     27.5   3.08                                  12   1424 AII   3.7 ± 0.2                                                                           1.8     12.5   3.55                                  ______________________________________                                    

                  TABLE V                                                         ______________________________________                                        Permeation of 253 AII through human cadaver                                   skin at 37° C. from different ointment formulations.                                     Flux     kp*10.sup.-6                                       Formulation       μg/cm.sup.2 h                                                                       cm/h                                               ______________________________________                                        253 AII base                                                                               50 mg    0.458    9.2                                            Ol. arach.(a)                                                                             100 mg                                                            Cetylan(b)  100 mg                                                            Aq. dest.(c)                                                                              750 mg                                                            253 AII      50 mg    0.066    1.3                                            PEG 1500(d)  60 mg                                                            PEG 400(e)  120 mg                                                            253 AII base                                                                               50 mg    1.965    39.3                                           Vaselin alb.                                                                              710 mg                                                            Paraffin liq.                                                                             240 mg                                                            ______________________________________                                         (a) Oleum arachideum                                                          (b) Cetylan, an emulgating wax                                                (c) Distilled water                                                           (d) Polyethylene glycol of average mol. weight 1500                           (e) Polyethylene glycol of average mol. weight 400                       

                  TABLE VI                                                        ______________________________________                                        Permeation of 1248 through human cadaver                                      skin at 37° C. from different ointment formulations.                                     Flux     kp*10.sup.-6                                       Formulation       μg/cm.sup.2 h                                                                       cm/h                                               ______________________________________                                        1248 base    50 mg    0.855    17.1                                           Ol. arach.  100 mg                                                            Cetylan     100 mg                                                            Aq. dest.   750 mg                                                            1248 base    50 mg    0.053    1.1                                            PEG 1500     60 mg                                                            PEG 400     120 mg                                                            1248 base    50 mg    2.217    42.6                                           Vaselin alb.                                                                              710 mg                                                            Paraffin liq.                                                                             240 mg                                                            ______________________________________                                    

                  TABLE VII                                                       ______________________________________                                        Example representing a transdermal patch                                      Composition                                                                   ______________________________________                                        A compound described in Table I either as a free                                                         1-20%                                              base or as a pharmaceutically acceptable salt thereof                         Vaselin alb.               about 20%                                          Paraffin                   about 5%                                           Silastic Elastomer 382 Medical grade*                                                                    about 55%                                          ______________________________________                                         *Dow Corning Corporation, USA                                            

The compound is added under thorough mixing to a mixture of vaselin andparaffin (mixture I). The silastic elastomer is weighed directly to atared mould to which mixture I is added and mixed throughly beforeadding the curing agent, catalyst M (Dow Corning). The formulation isallowed to cure for 48 h at room temperature and protected from light.

This formulation gives a flux rate through the skin in the range of 0.1to 2 μg/cm² h for the compounds as defined in claim 1.

We claim:
 1. A transdermal preparation comprising a therapeuticallyactive compound of the formula ##STR5## where R₁, R₂ and R₃ which can bethe same or different are H, CH₃, C₂ H₅ or Cl; X is CH═CH or (CH₂)_(n)where n is 1 to 3; and R₄ is hydrogen or a straight alkyl of 1 to 4carbon atoms.
 2. A preparation according to claim 1 which is in the formof an ointment, emulsion, gel, lotion, solution or cream.
 3. Apreparation according to claim 1 where the preparation is a transdermaldelivery system comprising a drug impermeable backing layer and anadhesive layer where the drug is dispersed in the adhesive layer.
 4. Apreparation according to claim 1 where the preparation is a transdermaldelivery system comprising a drug impermeable backing layer; an adhesivelayer and a matrix layer in which the drug is dispersed.
 5. Apreparation according to claim 4 where the matrix layer is made of apolymer material.
 6. A preparation according to claim 1 where thepreparation is a transdermal delivery system comprising a drugimpermeable backing layer; an adhesive layer; a drug permeable membranesealed to one side of said backing layer as to define at least one drugreservoir compartment therebetween and a drug or composition thereofwithin said drug reservoir.
 7. A preparation according to claim 1wherein R₁ is Cl and R₂ and R₃ which can be the same or different are H,CH₃, C₂ H₅ or Cl.
 8. A preparation according to claim 1 wherein thetherapeutically active compound is from Group (II).